Formulation

ABSTRACT

Granule formulation of quetiapine and pharmaceutically acceptable salt thereof are described, as are their preparation and their use in treating diseases of the central nervous system such as psychotic disease conditions including schizophrenia.

[0001] The present invention relates to a novel pharmaceuticalformulation comprising11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepineor a pharmaceutically acceptable salt thereof (hereinafter referred toas the “agent”), processes for its preparation, and its use. Inparticular the present invention relates to a formulation which iseasily suspended or dissolved in aqueous media.

[0002] The “agent” can be used to treat diseases of the central nervoussystem such as psychoses. A particular example of the “agent” isquetiapine fumarate (sold under the trade name Seroquel®). Quetiapinefumarate has been marketed for a number of years for the treatment ofschizophrenia and related disease conditions. A considerable body ofliterature describes how to use quetiapine fumarate. Specific referencesfor the preparation and use of the “agent” are European PatentApplication EP 240,228 and 282,236, U.S. Pat. No. 4,879,288 andInternational Patent Application WO 97/45124.

[0003] Quetiapine fumarate is marketed as a tablet. Although doctors,nurses and other carers try to ensure that the patient takes thetablet(s), in psychotic patients there is frequently a problem withnon-compliance. For example, the patient may “cheek” the tabletresulting in a missed dosage. Compliance problems would be reduced ifthe “agent” could be administered in the form of an oral solution orsuspension. An oral solution or suspension has the additional advantageof being easier to swallow and hence a better method of administrationfor those patients who have problems swallowing tablets.

[0004] To avoid problems with the “agent” deteriorating, the formulationof the present invention is provided as low moisture content granuleswhich are readily dissolved or suspended in aqueous media prior toadministration. The granules are also free flowing which enables uniformfilling and emptying of sachets so that an accurate dose of thetherapeutic product can be administered.

[0005] Various low moisture content formulations of the “agent” wereprepared but found to be unsuitable, because either the granules weretoo hard and therefore not easily dispersed, or were not free flowingand compacted upon standing or vibration.

[0006] Eventually we found a granule formulation of the “agent” whichwas free flowing and yet also surprisingly easily dissolved or suspendedin aqueous media. Thus, the present invention provides a granuleformulation of the “agent” which is free flowing and easily dissolved orsuspended in aqueous media. For example, it should be suitable foradministration within the time scale of the person administering thedose. Typically, it should be suitable for administration in less than15 minutes, preferably less than 5 minutes and more preferably in lessthan 2 minutes.

[0007] In particular, the present invention provides a granuleformulation comprising11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepineor a pharmaceutically acceptable salt thereof and a freely or verywater-soluble binder, wherein the granules have a bulk density range of0.15 g/ml to 0.60 g/ml and a tap density range of 0.20 g/ml to 0.70 g/mland 80% of the granules are in the size range of 75 to 850 microns.

[0008] The preparation, physical properties and beneficialpharmacological properties of the “agent” are described in publishedEuropean Patents EP 240,228 and 282,236 as well as in U.S. Pat. No.4,879,288, the entire contents of which are herein incorporated byreference.

[0009] Preferably the “agent” is11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepineor a highly water-soluble pharmaceutically acceptable salt thereof. Morepreferably the “agent” is11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][l,4]thiazepineor a dihydrochloride, maleate, citrate or a fumarate salt thereof. Mostpreferably the “agent” is quetiapine fumarate (Seroquel).

[0010] A freely or very water-soluble binder is a binder which dissolvesin less than 10 parts of water per 1 part of binder by weight andcomprises maltodextrin, mannitol, xylitol, pre-gelatin starch, sucroseor poly[1-(2-oxo-1-pyrrolidinyl)ethylene](povidone). Preferably thebinder dissolves in less than 1 part of water per 1 part of binder.

[0011] Preferably the very water-soluble binder is maltodextrin.

[0012] Preferably, the present invention provides a granule formulationcomprising Seroquel® and maltodextrin, wherein the granules have a bulkdensity range of 0.15 g/cc to 0.60 g/cc and a tap density range of 0.20g/cc to 0.7 g/cc and 80% of the granules are in the size range of 75 to850 microns.

[0013] Bulk density is the density of a free flowing powder. Tap densityis the density of the powder after it has been vibrated or tapped on asurface several times. Bulk density is determined by pouring a volume of100 ml of powder into a graduated cylinder and measuring the weight ofthe powder. Tap density is determined by placing the same cylinder,containing the 100 ml of powder used to measure the bulk density, on apiece of equipment that raises and drops the cylinder 200 times (theamplitude of the raising and lowering in this standard test is 0.5inches). The new volume of the powder is measured and since the weightof the powder is already known the tap density can be calculated.

[0014] Preferably the granules have a bulk density range of 0.261 g/mlto 0.400 g/ml; in particular 0.261 g/ml to 0.368 g/ml.

[0015] Preferably the granules have a tap density range of 0.342 g/ml to0.500 g/ml; in particular 0.342 g/ml to 0.464 g/ml.

[0016] Granules with the desired bulk density, tap density and sizerange characteristics can be formed by using a fluid bed process. Thefluid bed process involves fluidising the components of the formulationon a bed of air, adding water and then drying. Components of theformulation could alternatively be added as a solution or suspensionwith the water.

[0017] Accordingly, in another aspect, the present invention provides aprocess for preparing a formulation as defined above which comprises:

[0018] i) fluidising one or more components on a bed of air in a fluidbed;

[0019] ii) adding, to the fluid bed, water optionally containing one ormore components;

[0020] iii) drying.

[0021] Preferably the “agent” and the freely or very water-solublebinder and any other components are fluidised on the bed of air.

[0022] The fluid bed process is well known in the art, for example seeSchaefer T., Worts O., Control of Fluidized Bed Granulation I. Effect ofspray angle, nozzle height and starting materials on granule size andsize distribution, Arch. Pharm. Chemi Sci. Ed. 5, 1977, 51-60; SchaeferT., Worts O., Control of Fluidized Bed Granulation II. Estimation ofDroplet Size of Atomized Binder Solutions, Arch. Pharm. Chemi Sci. Ed.5, 1977, 178-193; Schaefer T., Worts O., Control of Fluidized BedGranulation III. Effects of Inlet Air Temperature and Liquid Flow Rateon Granule Size and Size Distribution. Control of Moisture Content onGranules in the Drying Phase, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 1-13;Schaefer T., Worts O., Control of Fluidized Bed Granulation IV. Effectsof Binder Solution and Atomization on Granule size and sizedistribution, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 14-25; Schaefer T.,Worts O., Control of Fluidized Bed Granulation V. Factors AffectingGranule Growth, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 69-82; Kawai S.,Granulation and Drying of Powdery or Liquid Materials by Fluidized BedTechnology, Drying technology, 11(4), 1993, 719-731; and Kokubo H.,Sunada H., Effect of Process Variable on the Properties and BinderDistribution of Granules Prepared in a Fluidized Bed, Chem. Pharm. Bull.45(6), 1997, 1069-1072.

[0023] The size and density of the granules can be affected by alteringconditions such as temperature, atomisation air pressure, process airvolume and water addition spray rate used in the fluid bed process. Akey parameter affecting the characteristics of the granules is themoisture level in the granules; this moisture level results from themoisture level that is built up in the fluid bed. Granules with thedesired characteristics can be obtained by altering the moisture levelbuilt up in the fluid bed using standard methods known in the art untilgranules of the appropriate size range and density are obtained. Forexample, on a 15 kg scale, the moisture level in the granules isnormally between 4 and 10%. Typical conditions on the 15 kg scale are aninlet air temperature of 55-70° C., an atomisation air pressure of 0.5to 3.5 bar, a process air volume of 150 to 225 cfm (cubic foot perminute) and a water addition spray rate of 100 to 150 ml/min. Granuleswith the desired physical characteristics could also be formed usingconditions outside these ranges. For example, on a larger scale (225Kg), granules according to the invention were prepared using an inletair temperature of 55-80° C., an atomisation air pressure of 1.0 to 3.0bar, a process air volume of 1600 to 2200 cfm and a water addition sprayrate of 600 to 900 ml/min.

[0024] In a preferred aspect, the present invention provides a fluid bedprocess wherein the moisture content is controlled to give granules witha moisture level in the range of 1.5 to 15%.

[0025] In another aspect, the present invention provides granules with amoisture level in the range of 1.5 to 15% preferably 3 to 10%, morepreferably 4 to 8%.

[0026] Preferably the moisture level in the fluid bed leads to granuleshaving a moisture level in the range 3 to 10%. More preferably themoisture level in the fluid bed leads to granules having a moisturelevel in the range 4 to 8%.

[0027] In a preferred aspect, the present invention provides a fluid bedprocess wherein the atomisation air pressure is in the range of 0.5 to3.5 bar, for example 1.0 to 3.0 bar.

[0028] In a further aspect, the present invention provides a granuleformulation comprising the “agent” and a freely or very water-solublebinder produced by a fluid bed process wherein the moisture level in thegranules before drying is in the range 1.5 to 15%.

[0029] In a preferred aspect, the present invention provides a granuleformulation comprising the “agent” and a freely or very water-solublebinder produced by a fluid bed process wherein the atomisation airpressure is in the range of 0.5 to 3.5 bar, for example 1.0 to 3.0 bar.

[0030] In a further aspect, the present invention provides a granuleformulation comprising the “agent” and a freely or very water-solublebinder, wherein the granules have a bulk density range of 0.15 g/ml to0.60 g/ml and a tap density range of 0.20 g/ml to 0.70 g/ml and 80% ofthe granules are in the size range of 75 to 850 microns; produced by afluid bed process.

[0031] Preferably, the present invention provides a granule formulationcomprising Seroquel® and maltodextrin, wherein the granules have a bulkdensity range of 0.1 5 g/ml to 0.60 g/ml and a tap density range of 0.20g/ml to 0.70 g/ml and 80% of the granules are in the size range of 75 to850 microns, produced by a fluid bed process.

[0032] Preferably the formulation contains a sweetener or sweeteners toenhance its taste. Suitable sweeteners include aspartame, MagnaSweet®,sucrose, saccharin, sodium cyclamate and acesultame potassium. Preferredsweeteners are aspartame and MagnaSweet®.

[0033] Other excipients such as suspending agents that are compatiblewith the “agent” could be added to the formulation to increase thelength of time that the formulation remains as a suspension in theaqueous media. Examples of suspending agents include sodium starchglycolate, starch, guar gum and povidone. However, we have found thatthe formulation dissolves or remains remarkably well suspended withoutthe need for suspending or thickening agents and this forms anotheraspect of the invention. For example, the 25 mg granule formulationdescribed in the Examples below surprisingly forms a solution in 30 mlof water in approximately 15-20 seconds. The 150 mg granule formulationdescribed in the Examples below forms a suspension in 30 ml of water inapproximately 10 seconds with gentle stirring and remains as asuspension for about 10 minutes. It can easily be re-suspended withgentle swirling in a matter of seconds.

[0034] Surprisingly, not only is a suspending agent generally notneeded, but also we have discovered that the typical suspending agent,xanthan gum, is generally not suitable as suspending agent in theformulations of the present invention.

[0035] Preferably the formulation does not include a suspending agent.

[0036] Likewise surfactants that are compatible with the “agent”, suchas polysorbates, glyceryl monooleate and sorbitan esters, can be addedto the formulation, but we have found that the granule formulationperforms well without the need for them.

[0037] Preferably the formulation does not include a surfactant.

[0038] Preferably, the present invention provides a granule formulationconsisting of11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepineor a pharmaceutically acceptable salt thereof, a freely or verywater-soluble binder and a sweetener, wherein the granules have a bulkdensity range of 0.15 g/ml to 0.60 g/ml and a tap density range of 0.20g/ml to 0.70 g/ml and 80% of the granules are in the size range of 75 to850 microns. In a preferred aspect11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepineis in the form of a fumarate salt.

[0039] The granules of the present invention are readily dissolved orsuspended in aqueous media. The aqueous media is not necessary water,but includes substances with a sufficient water content, for examplefruit/vegetable juices, sauces or purees such as desserts.

[0040] Preferably the pH of resulting solution/suspension is between pH4and pH9. More preferably, the pH of resulting solution/suspension isbetween pH5 and pH6.

[0041] In another aspect the invention relates to a granule formulationas defined above either dissolved or suspended in aqueous media.

[0042] The dose of the compound of the present invention which isadministered will necessarily be varied according to principles wellknown in the art taking account of the route of administration, theduration of treatment, the severity of the psychotic condition, the sizeand age of the patient, the potency of the active component and thepatient's response thereto. An effective dosage amount of the activecomponent can thus readily be determined by the clinician after aconsideration of all criteria and using his best judgement on thepatient's behalf. In general, the compound will be administered to awarm blooded animal (such as man) so that an effective dose is received,generally a daily dose in the range of about 0.01 to about 40 mg/kg bodyweight. For example, when administered orally, it is generallyadministered in the range of about 0.1 to about 40 mg/kg body weight.

[0043] Preferably, the compound of the present invention is administeredin about a 25, 50, 100, 125 or 150 mg strength.

[0044] It will be apparent to those skilled in the art that theformulation can be co-administered with other therapeutic orprophylactive agents and/or medicaments that are not medicallyincompatible therewith. The compound of the present invention does not,in general, show any indication of overt toxicity in laboratory testanimals at several multiples of the minimum effective dose of the activeingredient.

[0045] According to another aspect of the invention there is provided agranule formulation as defined above, for use as a medicament.

[0046] According to another aspect of the present invention there isprovided a method of treating psychosis, especially schizophrenia, byadministering an effective amount of a granule formulation as definedabove, to a mammal in need of such treatment.

[0047] The invention is further illustrated by the followingnon-limiting Examples in which temperatures are expressed in degreesCelsius. The “agent” may be prepared as described in published EuropeanPatents EP 240,228 or 282,236 as well as in U.S. Pat. No. 4,879,288.

EXAMPLES Example 1

[0048] Two different strength formulations were prepared. The firstcontained 25 mg of quetiapine free base (the 25 mg formulation) and thesecond 150 mg of quetiapine free base (the 150 mg formulation).

[0049] The composition of formulations is shown below: Ingredient 25 mg(mg/dose) 150 mg (mg/dose) Quetiapine fumarate  28.8 172.7 Maltodextrin,NF 950.0 767.3 Aspartarne, NF  21.2  30.0 MagnaSweet 135 ®  30.0Purified Water, USP q.s. (˜186.0) q.s. (˜186.0)

[0050] Quetiapine fumarate is equivalent to 86.8% quetiapine free base.Purified water was sprayed in a sufficient amount and manner to providegranules with a moisture content of 5.6%.

[0051] Maltodextrin may be purchased as Maltrin M-100 from, for example,Grain Processing Corporation. MagnaSweet 135® may be purchased fromMAFCO Worldwide Corporation.

[0052] The formulations were prepared using fluid bed technology. AGlatt GPCG-60 fluid bed processor is used on the 15 kg and 50 kg scale.A Glatt GPCG-300 fluid bed processor is used on the 225 kg scale. Thefluid bed processor was configured for top spray fluid bed granulationand as shown below: Apparatus Glatt GPCG-60 Glatt GPCG-300 Water PumpPeristaltic Peristaltic Inlet Air Dew Point 10° C. 10° C. Port Size  1.2mm  1.5 m Number of Ports in Nozzle Head 3 6 Nozzle Height #4 #4 BottomScreen 100 mesh 100 mesh Shake Mode GPCG GPCG Shake Interval  30 sec  60sec Shake Duration  3 sec  5 sec

[0053] The following processing conditions were used:

[0054] Glatt GPCG-60 Processing Parameters Pump Rate (g/min) InletProcess Air Atomisation Air Water Addition Batch Strength Temp (° C.)Volume (cfm) Pressure (bar) Spray Rate a  25 mg 65 850 2.0 360 b 150 mg65 850 2.0 360 c 150 mg 65 850 1.7 360 d 150 mg 65 850-750 1.5 360

[0055] Glatt GPCG-300 Processing Parameters Pump Rate (g/min) InletProcess Air Atomisation Air Water Addition Batch Strength Temp (° C.)Volume (cfm) Pressure (bar) Spray Rate a  25 mg ˜70 1850 2.0 800 b  25mg ˜70 1850 2.0 800 c 150 mg ˜70 1800 1.5 800 d 150 mg ˜70 1800 1.5 800

[0056] All of the ingredients were added to the fluid bed granulatorbowl. The material was then fluidized. After approximately 2 to 3minutes, water (186 ml per 1 gram of components) was sprayed into theexpansion chamber. The total processing time for each batch was lessthan one hour.

[0057] Results from the GPCG-60 (50 kg Scale) Sieve Analysis Data¹ -%Retained Density Moisture² ⁻ (μm) (g/ml) % Batch 850 425 250 180 150 75Pan Bulk Tap EOS³ Final⁴ a 0.4 4.8 19.8 21.8 11.1 31.6 10.5 0.29 0.399.3 5.4 b 0.3 22.0 13.7 20.0 11.7 38.9 13.2 0.36 0.35 7.9 3.8 c 0.2 3.318.2 21.9 10.8 33.1 12.5 0.34 0.41 7.4 4.3 d 1.6 12.2 28.9 20.0 7.7 19.110.5 0.31 0.42 8.7 5.9

[0058] Results from the GPCG-300 (225 kg Scale) Sieve Analysis Data¹ -%Retained (mesh) Density Moisture²- (μm) (g/ml) % Batch 850 425 250 180150 75 Pan Bulk Tap EOS³ Final⁴ a 2.8 13.1 33.4 23.8 10.1 13.0 3.8 0.260.35 6.2 6.0 b 1.7 12.2 32.9 25.3 9.9 15.7 2.3 0.26 0.28 7.5 6.7 c 2.517.6 33.6 19.5 9.5 11.3 6.0 0.36 0.42 6.7 5.3 d 5.8 23.9 32.7 17.2 8.38.0 4.1 0.29 0.37 7.4 6.6

Example 2

[0059] The formulations from Example 1 above are filled into sachets ina conventional manner.

1. A granule formulation comprising11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo [b,f][1,4]thiazepine or a pharmaceutically acceptable salt thereof and a freely orvery water-soluble binder, wherein the granules have a bulk densityrange of 0.15 g/cc to 0.60 g/cc and a tap density range of 0.20 g/cc to0.70 g/cc and 80% of the granules are in the size range of 75 to 850microns.
 2. A formulation according to claim 1 wherein11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine is in the form of a fumarate salt.
 3. A formulation accordingto either claim 1 or claim 2 wherein the freely or very water-solublebinder comprises maltodextrin, mannitol, xylitol, pre-gelatinisedstarch, surcrose or poly[1-(2-oxo-1-pyrrolidinyl)ethylene].
 4. Aformulation accroding to claim 3 wherein the binder is maltodextrin. 5.A formulation according to claim 1 wherein the bulk density range is0.26 g/cc to 0.400 g/cc d the tap density range is 0.342 g/cc to 0.500g/cc.
 6. A formulation according to claim 1 which further comprises asweetener. 7-8.
 9. A formulation according to claim 1 wherein themoisture level in the granules is between 1.5 and 15%.
 10. A formulationaccording to claim 9 wherein the moisture level in the granules isbetween 4 and 8%.
 11. A process for preparing a formulation as definedin claim 1 which process comprises i) fluidising one or more componentson a bed of air in a fluid bed; ii) adding to the fluid bed, wateroptionally containing one or more components; iii) drying.
 12. A processaccording to claim 11 wherein11-[4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl]dibenzo[b,f][1,4]thiazepine or pharmaceutically acceptable salt thereof and the freely orvery water-soluble binder are fluidised on a bed of air.
 13. A granuleformulation as defined in claim 1 for use in a method of therapeutictreatment of a patient in need thereof.
 14. Use of a granule formulationas defined in claim 1 in the manufacture of a medicament for thetreatment of diseases of the central nervous system, such as psychoses,in particular schizophrenia.
 15. A method for treating diseases of thecentral nervous system, such as psychoses, in particular schizophrenia,which comprises administering an effective amount of a formulation asdefined in claim 1 to a patient in need thereof.
 16. A kit comprising i)a granule formulation as defined in claim 1; ii) an aqueous medium; iii)optionally, instructions for use so that the granules can be dissolvedor suspended in said aqueous medium for administration.
 17. A sachetcontaining a granule formulation as defined in claim 1.